1. Field of the Invention
This invention relates to the inhibition of flagellated parasitic protozoa Trypanosoma and Leishmania with camptothecin compounds. Camptothecin compounds have the ring structure shown below. ##STR1## The invention also relates to the treatment of animals having hemoflagellate infections with camptothecin compounds.
2. Background of the Invention
The hemoflagellates include organisms of the genera Trypanosoma and Leishmania.
Organisms of the genus Trypanosoma are hemoflagellates which infect livestock, wild animals and humans causing trypanosomiasis. Diseases associated with trypanosomiasis include sleeping sickness, Chagas' Disease and asymptomatic trypanosomiasis. Trypanosomiasis is particularly prevalent in African and South American countries.
Current therapy for trypanosomiasis has many drawbacks. The existing pharmaceuticals for treating trypanosomiasis in humans include suramin, pentamidine, stilbamidine, propamidine, melarsoprol, nitrofurazone and the trivalent arsenicals. These drugs are toxic and generally must be administered parenterally. Trypanosome strains resistant to these drugs are now emerging. A more recent pharmaceutical introduced into clinical use is .alpha.-difluoromethylornithine. See Bacch, C. J. et a.l. (1980) Science, 210:332-334. This compound is available on a limited basis only, however, and requires repeated high parenteral doses to effect a cure. Additionally, this compound is ineffective against Rhodesian sleeping sickness.
Conventional therapy for livestock and other domestic animals includes treatment with diminazene aceturate (berenil), isometamidium chloride (samorin) and ethidium bromide. See Williamson, J. (1970) in The African Trypanosomiases (Mulligan, H. W., Ed.) pages 125-221, Wiley-Interscience, Great Britain.
Organisms of the genus Leishmania are hemoflagellates which are closely related to trypanosomes and are the causative agent of the disease leishmaniasis. This disease is spread by the bite of sand flies, and on a worldwide basis, afflicts millions of persons. In recent years, American soldiers serving in Panama, the middle east and East Africa have returned home with leishmaniasis. Untreated, some forms of leishmaniasis, notably visceral leishmaniasis are fatal.
Current therapy for leishmaniasis includes pentavalent antimonials, pentamidine, and amphotericin B, all of which have substantial toxicity. See Neva, F. and Sacks, D. (1990) in Tropical and Geographical Medicine, 2nd Ed. (Warren, K. S. and Mahmoud, A. A. F., Eds.) pages 296-308, McGraw-Hill, N.Y.
A need continues to exist for new compounds which are toxic to hemoflagellates and useful in treating trypanosomiasis and leishmaniasis.